Various drugs and other useful chemicals are known to have the side effect of causing renal damage. In the case of drugs, this places undesirable restrictions on the amount of the drug that can be used and the frequency of use, and limits use of the drug to patients who can tolerate the side effects. Even where the short term benefits of using the drug outweigh the problems caused by the side effects, and where the patient is willing to tolerate the side effects, such drugs can adversely affect the patient's long term health. In the case of non-drug chemicals (e.g. work place chemicals, radiation contrast media), nephrotoxic effects can in an analogous manner require exposure to the chemicals to be limited.
There have in the past been various attempts to determine the chemical and biological causes of chemically-induced nephrotoxicity, and attempts to develop means for blocking or reducing these effects. See generally J. Burchenal et al., 60 Biochim. 961-965 (1978); J. Filipski et al., 204 Science 181-183 (1979); J. Yuhas et al., 64 Can. Treat. Rep. 57-64 (1980); S. Howell et al., 43 Can. Res. 1426-1431 (1983); C. Kuo et al., 67 Tox. Ap. Pharm 78-88 (1983); A. Elfarra et al., 33 Biochem. Pharm. 3729-3732 (1984); A. Elfarra et al., 233 J. Pharm. Ex. Therap. 512-516 (1985); L. Ramsammy et al., 34 Biochem. Pharm. 3895-3900 (1985); P. Williams et al., 237 J. Pharm. Ex. Therap. 919-925 (1986); P. Dedon et al., 36 Biochem. Pharm. 1955-1964 (1987); S. Heyman et al., 82 J. Clin. Invest. 401-412 (1988); R. Qazi et al., 80 J. Natl. Can. Ins. 1486-1488 (1988); B. Tune et al., 38 Biochem Pharm. 795-802 (1989); A. Berns, Nephrology Forum, Kidney International, Vol. 36, pp. 730-740 (1989). The disclosure of these articles and all other articles described herein are incorporated by reference as if fully set forth herein. However, means for reducing nephrotoxicity are typically ineffective, overly expensive, and/or have their own side effects.
In other unrelated work, methimazole (1-methyl-2-mercaptoimidazole) has been used since the early 1940s in connection with thyroid treatment. See generally B. Marchant et al., 91 Endo. 747-756 (1972). It has also been reported that methimazole inhibits prostaglandin H synthase-dependent oxidation. See generally T. Petry et al., 262 J. Biol. Chem. 14112-14118 (1987) and T. Zenser et al., 227 J. Pharm. Ex. Therap. 545-550 (1983).
A few recent reports also describe the effects of methimazole on 2-bromohydroquinone ("BHQ") activity using renal tubules or homogenates. See S. Lau et al., 15 Drug Met. Disp. 801-807 (1987) (BHQ nephrotoxicity may be related to prostaglandin synthesis); R. Schnellmann et al., 237 J. Pharm. Exp. Ther. 456, 459 (1986) (does not protect against BHQ in vitro toxicity); R. Schnellmann, 99 Tox. App. Pharm 11, 12 (1989) (BHQ oxidation probably unrelated to prostaglandin synthesis).
Notwithstanding the over forty years of experience with methimazole, and the many years of attempts to solve nephrotoxicity side effects, a need still exists for improved means for better protecting kidneys against nephrotoxic chemicals.